TY - JOUR
T1 - Dynamic structural determinants underlie the neurotoxicity of the N-terminal tau 26-44 peptide in Alzheimer's disease and other human tauopathies
AU - Perini, Giordano
AU - Ciasca, Gabriele
AU - Minelli, Eleonora
AU - Papi, Massimiliano
AU - Palmieri, Valentina
AU - Maulucci, Giuseppe
AU - Nardini, Matteo
AU - Latina, Valentina
AU - Corsetti, Veronica
AU - Florenzano, Fulvio
AU - Calissano, Pietro
AU - De Spirito, Marco
AU - Amadoro, Giuseppina
PY - 2019
Y1 - 2019
N2 - The intrinsically disordered tau protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and other human tauopathies. Abnormal post-translational modifications of tau, such as truncation, are causally involved in the onset/development of these neurodegenerative diseases. In this context, the AD-relevant N-terminal fragment mapping between 26 and 44 amino acids of protein (tau26-44) is interesting, being endowed with potent neurotoxic effects in vitro and in vivo. However, the understanding of the mechanism(s) of tau26-44 toxicity is a challenging task because, similarly to the full-length tau, it does not have a unique 3D structure but exists as dynamic ensemble of conformations. Here we use Atomic Force Spectroscopy, Small Angle X-ray Scattering and Molecular Dynamics simulation to gather structural and functional information on the tau26-44. We highlight the presence, the type and the location of its temporary secondary structures and we unveil the occurrence of relevant transient tertiary conformations that could contribute to tau26-44 toxicity. Data are compared with those obtained on the biologically-inactive, reverse-sequence (tau44-26 peptide) which has the same mass, charge, aminoacidic composition as well as the same overall unfolded character of tau26-44.
AB - The intrinsically disordered tau protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and other human tauopathies. Abnormal post-translational modifications of tau, such as truncation, are causally involved in the onset/development of these neurodegenerative diseases. In this context, the AD-relevant N-terminal fragment mapping between 26 and 44 amino acids of protein (tau26-44) is interesting, being endowed with potent neurotoxic effects in vitro and in vivo. However, the understanding of the mechanism(s) of tau26-44 toxicity is a challenging task because, similarly to the full-length tau, it does not have a unique 3D structure but exists as dynamic ensemble of conformations. Here we use Atomic Force Spectroscopy, Small Angle X-ray Scattering and Molecular Dynamics simulation to gather structural and functional information on the tau26-44. We highlight the presence, the type and the location of its temporary secondary structures and we unveil the occurrence of relevant transient tertiary conformations that could contribute to tau26-44 toxicity. Data are compared with those obtained on the biologically-inactive, reverse-sequence (tau44-26 peptide) which has the same mass, charge, aminoacidic composition as well as the same overall unfolded character of tau26-44.
KW - Alzheimer Disease
KW - Alzheimer's disease (AD)
KW - Amino Acid Sequence
KW - Animals
KW - Atomic Force Microscopy (AFM)
KW - Humans
KW - Microscopy, Atomic Force
KW - Molecular Dynamics (MD) simulation
KW - Molecular Dynamics Simulation
KW - Neurons
KW - Peptides
KW - Protein Conformation
KW - Rats
KW - Small Angle X-ray Scattering (SAXS)
KW - Structure-Activity Relationship
KW - Tau protein
KW - Tauopathies
KW - X-Ray Diffraction
KW - tau Proteins
KW - Alzheimer Disease
KW - Alzheimer's disease (AD)
KW - Amino Acid Sequence
KW - Animals
KW - Atomic Force Microscopy (AFM)
KW - Humans
KW - Microscopy, Atomic Force
KW - Molecular Dynamics (MD) simulation
KW - Molecular Dynamics Simulation
KW - Neurons
KW - Peptides
KW - Protein Conformation
KW - Rats
KW - Small Angle X-ray Scattering (SAXS)
KW - Structure-Activity Relationship
KW - Tau protein
KW - Tauopathies
KW - X-Ray Diffraction
KW - tau Proteins
UR - http://hdl.handle.net/10807/155256
U2 - 10.1016/j.ijbiomac.2019.08.220
DO - 10.1016/j.ijbiomac.2019.08.220
M3 - Article
SN - 0141-8130
VL - 141
SP - 278
EP - 289
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -